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Biomedical subjects

I MacIntyre

Publications and source records attributed to I MacIntyre.

At least 91 records · Page 5Linked to original sources
PubMed1986

The calcitonin-like sequence of the beta CGRP gene.

We have identified a region within the beta CGRP gene which has the potential to encode a novel calcitonin-like peptide. The gene is located on the short arm of chromosome 11 (11p 12-14.2) and we suggest that it resulted from a local duplication of the alpha gene. We have been unable to detect the corresponding mRNA in a variety of tissues which express alpha-calcitonin. It is not clear whether this sequence can be expressed in man.

Base Sequence↗
PubMed1986

Ultrastructural observation of nerve fibers containing both substance P and calcitonin gene-related peptide in the nucleus tractus solitarii of the rat: a combination of immunofluorescence and PAP methods.

Nerve fibers and their axon terminals with substance P (SP)-like and calcitonin gene-related peptide (CGRP)-like immunoreactivity in the nucleus tractus solitarii were ultrastructurally characterized by a combination of immunofluorescent double staining and the PAP method. The axon terminals formed asymmetrical synaptic contacts with other non-reactive neuronal elements (perikarya, dendritic shafts and dendritic spines). Some terminals received synaptic inputs from non-reactive axon terminals. This suggests that some, if not all, afferents containing SP and CGRP are affected presynaptically by other afferents.

Animals↗
PubMed1986

Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains.

125I-calcitonin gene-related peptide (CGRP) binding sites were mapped in the human brain and rat brains by in vitro macroautoradiography, and compared to each other. Binding experiments were made to characterize 125I-CGRP binding on the human and rat brains. Scatchard analysis of saturation experiments from slide-mounted sections of the human and rat cerebellum displayed 125I-CGRP binding sites with a dissociation constant (Kd) of 0.17 nM and 0.11 nM, respectively, and a maximal number of binding sites (Bmax) of 96.8 fmol/mg and 23.0 fmol/mg protein. 125I-CGRP binding was time-dependent, reversible and saturable with high affinity in the brains. Autoradiograms showed a discrete distribution of 125I-CGRP binding sites throughout the brains of human and rat with patterns similar to each other. In the human brain, the highest binding was seen in the cerebellum, inferior olivary nuclear complex, certain parts of the central gray matter, arcuate nuclei of the medulla oblongata and dorsal motor nucleus of the vagus, and densities of CGRP-binding sites were high in the nucleus accumbens, amygdala, tail of the nucleus caudatus, substantia nigra, ventral tegmental area, medial portion of the inferior colliculus, medial pontine nuclei, locus coeruleus, inferior vestibular nucleus, substantia gelatinosa of the spinal trigeminal nucleus, nucleus of the solitary tract and nucleus cuneatus lateralis. In the rat, high densities were found in the hippocampus pars anterior, nucleus accumbens, ventral and caudal portions of the nucleus caudatus-putamen, central and basolateral nuclei of the amygdala, caudal portion of the insular cortex, medial geniculate body, superior and inferior colliculi, certain portions of the central gray matter, locus coeruleus, inferior olivary nuclei, vagal complex, nucleus cuneatus lateralis and cerebellum. In contrast, in both species, most of the cortical areas including the hippocampus, most of the thalamus, and hypothalamus exhibited few binding sites. In addition, high quantities of the binding sites were seen on the pia mater and on walls of blood vessels in the brain and subarachnoidea. These results revealed essentially homologous locations of CGRP binding sites in the human and rat central nervous systems and well corresponding distributions of binding sites and endogenous CGRP-like immunoreactivity.

Aged↗
PubMed1986

A second form of human calcitonin gene-related peptide which is a potent vasodilator.

A recently predicted form of human calcitonin gene-related peptide, (beta CGRP) exhibits potent vasodilator activity in rabbit skin with a similar potency to the form of human CGRP originally described (alpha CGRP). Both peptides, because of their vasodilator activity, cause a potentiation of inflammatory oedema induced by mediators of increased vascular permeability. The results demonstrate that changes can be made at certain positions in the amino acid sequence of human CGRP without loss of vasodilator activity.

Amino Acid Sequence↗
PubMed1986

Two distinct calcitonin gene-related peptide-containing peripheral nervous systems: distribution and quantitative differences between the iris and cerebral artery with special reference to substance P.

The present study first shows that calcitonin gene-related peptide(CGRP)-like immunoreactive (CGRPI) nerve fibers in the cerebral arteries contained substance P (SP) and originated from small- to medium-sized CGRPI cells exhibiting SP immunoreactivity (SPI) in the trigeminal ganglion. The iris contained CGRPI/SPI-costorage nerve fibers and many CGRPI fibers lacking SPI. These fibers originated from large CGRPI cells lacking SPI in the trigeminal ganglion. The heterogenous subpopulations of CGRPI fibers in the iris suggest that CGRP is involved in a variety of functions in this structure.

Animals↗
PubMed1986

Origins and distribution of calcitonin gene-related peptide-containing nerves in the wall of the cerebral arteries of the guinea pig with special reference to the coexistence with substance P.

The origins and overall distribution of calcitonin gene-related peptide-like immunoreactivity (CGRPI) in the wall of the cerebral arteries were investigated in the guinea pig by using whole-mounts. Two types of CGRPI fibers were seen; one forming dense fiber bands, located among the periadventitial nerves, and the other forming a meshwork. CGRPI fibers in the periadventitial nerves often leave these nerves to form a meshwork, of a density that varies according to the diameter or location of the blood vessel. The present study showed that CGRPI fibers in the walls of the carotid arterial system originated from the trigeminal ganglion, and those in the vertebrobasilar arterial system from other origins besides the trigeminal ganglion. We also examined the coexistence of this peptide with substance P-like immunoreactive (SPI) structures in a single neuron system. Double staining immunocytochemistry showed that the patterns of the running of CGRPI and SPI fibers in the wall of the cerebral arteries were similar, and this method also demonstrated the presence of neurons containing both CGRPI and SPI structures in single cells of the trigeminal ganglion, which is the major origin of these fibers in the cerebral arteries.

Animals↗
PubMed1986

Investigation of the structure/activity relationship of human calcitonin gene-related peptide (CGRP).

The biological activities of calcitonin gene-related peptide (CGRP) enzymic digest fragments, chemically modified products and beta-CGRP have been compared to that of intact alpha-CGRP on rat isolated paired atria. Tryptic and chymotryptic digests both produced inactive fragments. Acetylation of the N-terminal amino acid (Alanine) or either of Lys 24 or Lys 35, resulted in reduced, but measurable, biological activity. Destruction of the disulphide bridge between Cys 2 and Cys 7 abolished biological activity. Substitution of several amino acids, Asp 3, Val 22 and Asn 25, with Asn, Met and Ser respectively (beta-CGRP), produced a peptide with similar biological activity to alpha-CGRP.

Amino Acids↗
PubMed1986

Distribution of calcitonin gene-related peptide-containing fibers in the urinary bladder of the rat and their origin.

By use of indirect immunofluorescence, this study demonstrated the presence of calcitonin gene-related peptide-like immunoreactive (CGRPI) fibers in the bladder of the rat. These fibers were abundant in the muscle layer, in which they ran parallel to the muscles, submucosa, and epithelium. No immunoreactive cells were detected. We also examined the origins of these fibers, using a method that combined biotinized retrograde tracer (biotin-wheat germ agglutinin) (B-WGA) and immunocytochemistry. Injection of the tracer into the bladder resulted in the demonstration of small to medium-sized labeled cells that contain CGRPI structures in single dorsal root ganglion cells mostly at the level of L6 and S1, but also a few at L2. Double-staining for CGRPI and immunoreactive P-like substance (SPI) indicated that there are cells in the dorsal root ganglia at the level of L6 and S1 that react to both, but that there are many CGRPI-positive cells that contain no demonstrable SPI; most of the latter are large.

Animals↗
PubMed1986

The presence of a calcitonin gene-related peptide in the olivocochlear bundle in rat.

The origins of calcitonin gene-related peptide immunoreactive (CGRPI) fibers in the cochlea were examined in rats. Parasagittal transection of the brain just medial to the principal sensory trigeminal nucleus resulted in the ipsilateral disappearance of CGRPI fibers in the cochlea, indicating that the origins of these fibers lie in the central nervous system. Next, we used a highly sensitive method combining retrograde tracing and immunohistochemistry to identify the origins of the CGRPI fibers in the cochlea. After injection of biotin-wheat germ agglutinin (b-WGA) into the cochlea, CGRPI neurons in the ipsilateral lateral superior olivary nucleus also contained b-WGA granules. These findings indicated that CGRPI efferent fibers are major components of the olivocochlear bundle.

Animals↗
PubMed1986

Ontogeny of calcitonin gene-related peptide and calcitonin in the rat thyroid.

In this immunohistochemical study, the ontogenic development of calcitonin-gene-related peptide (CGRP) in the rat thyroid was investigated and compared with that of calcitonin using the indirect-immunofluorescence method. Parafollicular cells with immunoreactivity to both CGRP and calcitonin first appeared at an early stage of gestation (days 17 and 18) in the central portion of the thyroid. Cells immunoreactive to CGRP and calcitonin had became numerous by gestational day 22. After postnatal day 7, CGRP- and calcitonin-immunoreactive (C-IR) cells increased rapidly both in number and in the intensity of their fluorescence. In 14- to 90-day old rats, many intensely immunoreactive cells were distributed in the central portion of the thyroid. The cells immunoreactive to CGRP and to calcitonin had an almost identical ontogenic appearance. In 14-day-old and adult rats, C-IR cells also exhibited CGRP immunostaining, suggesting that these cells simultaneously produce and store CGRP during ontogeny.

Aging↗
PubMed1986

Human calcitonin gene related peptide: a potent endogenous vasodilator in man.

In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 +/- 5 to 55 +/- 7 mmHg (P less than 0.05), the heart rate to increase from 61 +/- 7 to 87 +/- 5 beats/min (P less than 0.05) and the skin temperature to increase from 33.7 +/- 0.9 to 34.9 +/- 0.5 degrees C. Plasma noradrenaline increased from 481 +/- 126 to 835 +/- 65 pg/ml (P less than 0.05) and plasma adrenaline from 57 +/- 17 to 82 +/- 12 pg/ml (P less than 0.05). There were no significant changes in the albumin-corrected plasma calcium. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

Adult↗
PubMed1986

Potent vasodilator activity of calcitonin gene-related peptide in human skin.

We have recently shown that the novel neuropeptide calcitonin gene-related peptide, CGRP, is a potent vasodilator. In this paper we report a detailed study of the effects of CGRP in human skin. CGRP induces a clearly defined, long-lasting erythema. We have measured the effect of CGRP on blood flow in human skin using a laser Doppler technique and have demonstrated increased local blood flow that persists for a number of hours. We compared the response of CGRP with other known vasodilators [histamine, prostaglandin (PG) E2, PGI2, substance P, and vasoactive intestinal peptide (VIP)] in the skin, and in all subjects the erythema induced by CGRP was more persistent than that induced by the other mediators tested. Except at high doses the local vasodilatation induced by CGRP was not associated with a wheal and flare as seen with histamine, substance P, and VIP. CGRP is an extremely potent vasodilator and if released into the circulation, or locally from peripheral nerve endings, it could have a role in the regulation of blood flow in both physiologic and pathologic conditions; CGRP may be the endogenous mediator of the flare in the triple response. A deficiency in CGRP secretion or action could be an important component of peripheral vascular disease. Some flushing reactions (e.g., those associated with medullary thyroid carcinoma) may result from circulating CGRP.

Adult↗
PubMed1986

Calcitonin gene-related peptide: a potent dilator of human epicardial coronary arteries.

To investigate the action of calcitonin gene-related peptide (CGRP) on human epicardial coronary arteries, six patients received intracoronary CGRP at doses of 50,100, and 200 ng/min. The effect of CGRP was measured angiographically with a computerized analysis system. A dose-dependent increase in coronary arterial diameter was observed. At the highest dose there were 34%, 7%, 38%, and 40% mean increases in the diameters of the circumflex, proximal, mid, and distal left anterior descending arteries, respectively. No further increase in diameter was found after a subsequent dose of 1 mg intracoronary isosorbide dinitrate. Prior infusion of CGRP did not prevent coronary arterial spasm induced by ergonovine in two patients with variant angina, but a subsequent bolus of CGRP partially relieved the spasm. We propose that CGRP has a role in the regulation of coronary vascular smooth muscle tone.

Angina Pectoris↗
PubMed1986

Human synthetic calcitonin gene-related peptide inhibits bone resorption in vitro.

The calcitonin gene-related peptide (CGRP) is a peptide which normally circulates. It is encoded by the calcitonin gene, whose precise function is unknown. Since it has recently been shown that human CGRP (hCGRP) lowers plasma calcium levels in both the rat and the rabbit, we examined the in vitro effects of human synthetic CGRP on bone resorption (as measured by 45Ca release) stimulated by PTH, prostaglandin E2, and 1,25-dihydroxyvitamin D3. CGRP caused a dose-dependent inhibition of PTH-stimulated resorption, with 50% inhibition at approximately 5 X 10(-8) M CGRP. The inhibitory effects of CGRP on PTH-mediated bone resorption were not due to toxic effects, since bones preincubated with CGRP for 48 h were subsequently able to respond to PTH. The inhibitory activity of CGRP in the rat was approximately 3 orders of magnitude less potent than that of human calcitonin. In contrast to the effects of calcitonin, a marked inhibition of PTH-stimulated bone resorption was still observed after 96 h in the continued presence of CGRP. CGRP (10(-6)-10(-8) M) also inhibited resorption stimulated by prostaglandin and 1,25-dihydroxyvitamin D3 in a dose-dependent manner, but had no significant effect on basal bone resorption. In conclusion, these data show that hCGRP inhibits hormone-stimulated bone resorption in vitro. Although it is less potent than calcitonin in the rat, CGRP has been shown to have potency comparable to that of calcitonin in other species, and therefore, a role for CGRP as a therapeutic agent in states of increased bone resorption cannot be ruled out.

Animals↗
PubMed1986

The origin of circulating calcitonin gene-related peptide in the rat.

It is known that in addition to the calcitonin precursor the calcitonin gene also encodes a novel peptide, calcitonin gene-related peptide (CGRP). This potent vasodilator has been found in the circulation of man. This present study demonstrates that CGRP is also found in the circulation of the rat and that plasma CGRP comes from two different sources: the thyroid, a major source in old rats, and the perivascular nerves probably at all ages.

Adrenal Glands↗
PubMed1985

Localization of calcitonin gene-related peptide in the organ of Corti of the rat: an immunohistochemical study.

The localization of calcitonin gene-related peptide (CGRP)-like immunoreactive (CGRPI) structures in the cochlea was examined in the rat using immunocytochemistry. Numerous CGRPI fibers entered the organ of Corti in the intraganglionic spiral bundle and formed a dense fiber patch at the base of the inner hair cells. Much fewer, but still a significant number of CGRPI fibers were seen at the synaptic region of the outer hair cells. Since no immunoreactive cells were seen in the organ of Corti and spinal ganglion, these fibers may be one of the major components of the olivocochlear bundles originated from the superior olivary complex.

Animals↗